The biomedical value of identifying the genes and variants responsible for Mendelian disorders is extraordinarily high. The clinical manifestations of these disorders involve virtually all organ systems and their developmental and physiological parameters. About half of recognized Mendelian disorders (as enumerated in the OMIM database) remain unexplained at the molecular level and many more of these remain to be recognized. Over the last 3.25 years, the Baylor College of Medicine and the Johns Hopkins University School of Medicine human genetics programs have combined and formed the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) to find Mendelian genes. In doing so, we have taken advantage of the synergies afforded by combining our expertise in clinical genetics, genomic technologies, genetic analysis and understanding the biological basis of genetic disease. We have met and will continue to meet the challenge of research subjects by utilizing our worldwide network of colleagues and former trainees. Using state of the art genomic methods and analytic tools, we have already sequenced the exome or the genome of 5,443 individuals, identifying 169 novel disease genes in the first 3.25 years of funding, and have more than 4,000 samples ready to sequence from collaborators in the USA and >20 other countries. In the future, we will expand this network of collaborators to identify even more samples. We have also developed automated processes to contact the authors of publications from unexplained Mendelian disorders in OMIM to recruit additional specific disease examples. We have designed and passed through the IRB an online consenting process that bypasses the bottlenecks of time difference and language in international and remote site recruiting. To streamline and monitor our progress we have developed PhenoDB, a web-based tool for the collection, storage and analysis of disease, phenotypic feature and genotype information. PhenoDB also tracks samples, and is updated with the deliberations of our expert committees for Phenotype Review and ELSI issues. We have and will continue to build on our existing high throughput sequencing pipelines and have developed integrated laboratory and analysis efforts with experts from both institutions to develop new methods and software to advance the field. We have and will disseminate the phenotype and molecular information through publication, lectures, posting to communal websites and dbGaP. To connect clinicians and scientists with interest in the same gene and accelerate confirmation of novel disease gene identification, we developed GeneMatcher, now part of the MatchMaker Exchange initiative involving geneticists around the world. Going forward, to educate health care providers and trainees, we plan to develop a Massive Open Online Course in genetics, and to educate the public while enhancing recruitment, we will develop a set of online educational videos.